BCR/ABL can promote CD19+ cell growth but not render them long-term stemness.
BCR/ABL can promote CD19+ cell growth but not render them long-term stemness.
复制标题
DOI：
10.21037/sci.2016.11.06
复制
发表时间：
2016-01-01
影响因子：
--
通讯作者：
Ren, Ruibao
中科院分区：
文献类型：
--
作者：
Li, Donghe;Zhao, Xuemei;Ren, Ruibao
背景：肿瘤干细胞是具有自我更新和重建肿瘤细胞能力的恶性肿瘤细胞亚群。根除肿瘤干细胞是治疗恶性肿瘤的关键。既往造血系统恶性肿瘤的研究表明，慢性髓细胞性白血病（CML）慢性期的白血病干细胞（LSC）来源于造血干细胞（HSC），而急性髓细胞性白血病（AML）中的LSC既可以来源于HSC，也可以由髓系祖细胞转化而来。但在B细胞急性淋巴细胞白血病（B-ALL）中，白血病干细胞的来源尚不清楚。方法：将BCR/ABL逆转录病毒感染的骨髓细胞或CD 19+细胞移植到受体小鼠体内，建立B淋巴细胞白血病小鼠模型。在二次或三次移植实验中，GFP+细胞（白血病细胞）从原发性或继发性B-ALL小鼠中分离。结果：BCR/ABL基因转染CD 19+细胞后，在体外可促进其集落形成，在体内可诱导B-ALL样疾病。然而，只有BCR/ABL转导的全骨髓细胞可以多次移植到受体小鼠体内，后者的长期LSC频率为1/135 ~ 1/629。这些研究表明，BCR/ABL不能赋予定向B淋巴祖细胞长期的干细胞性，并暗示CD 19嵌合抗原受体（CAR）改良的T细胞疗法可能不能有效根除BCR/ABL+ B-ALL中的LSC。
BACKGROUND: Cancer stem cells are a subpopulation of malignant cells that have the capacity of both self-renewal and reconstitution of the cancer. Eradication of cancer stem cells is crucial for curing the malignant disease. Previous studies in hematopoietic malignancies showed that leukemia stem cells (LSCs) in chronic myelogenous leukemia (CML) chronic phase are originated from a hematopoietic stem cell (HSC), while LSCs in acute myeloid leukemia (AML) can either be derived from HSCs or be transformed from myeloid progenitors. But in B-cell acute lymphoblastic leukemia (B-ALL), the origin of leukemia stem cells is not clear. In this study, we tested whether BCR/ABL could transform B-lineage committed CD19+ cells to LSCs.METHODS: The B-cell lymphoblastic leukemia mouse model was generated by transplanting BCR/ABL-containing retrovirus infected bone marrow (BM) cells or CD19+ cells into recipient mice. In the secondary or tertiary transplantation experiment, the GFP+ cells (leukemic cells) were isolated from primary or secondary B-ALL mice. In addition, the frequency of leukemia stem cells was determined by limited dilution assay.RESULTS: We found that transducing BCR/ABL in CD19+ cells can promote their colony formation in vitro and induce B-ALL like disease in vivo. However, only BCR/ABL transduced whole BM cells can be transplanted multiple times in recipient mice, and the frequency of long-term LSCs from the latter ranges from 1/135 to 1/629.CONCLUSIONS: These studies suggest that BCR/ABL is unable to confer the long-term stemness to committed B-lymphoid progenitors and imply that CD19 chimeric antigen receptor (CAR) modified T cell therapy may not be effective in eradicating LSCs in BCR/ABL+ B-ALL.